Strontium phosphate microparticle for radiological imaging and therapy

ABSTRACT

This invention relates to strontium-phosphate microparticles that incorporate radioisotopes for radiation therapy and imaging.

CROSS REFERENCE TO RELATED APPLICATIONS

Not applicable.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

No federal government funds were used in researching or developing thisinvention.

NAMES OF PARTIES TO A JOINT RESEARCH AGREEMENT

Not applicable.

SEQUENCE LISTING INCLUDED AND INCORPORATED BY REFERENCE HEREIN

Not applicable.

BACKGROUND Field of the Invention

The field of the present invention is radiomicroparticles for medicaltherapy and imaging, and particularly radioactive strontium phosphatemicroparticles for radiological imaging and radioisotope therapy.

In the treatment of patients with certain kinds of cancer or rheumatoidarthritis, methods are known in which radioactive particles areintroduced intravascularly to a tumor site (radioembolism) or locallyinto the synovial fluid in a joint in order to trap the radioactiveparticle at a particular site for its radiation effect. Similar methodsare used for imaging parts of the body, organs, tumors, and so forth.

According to this technique, a quantity of the radioactive particles areinjected into a localized area of the patient to be imaged and/ortreated. For imaging, gamma emitting materials are commonly used tolabel carriers that provide imaging of a tissue area, tumor or organ.Some of these carriers have a specific affinity for certain bindingsites or biochemical targets allowing target specific or locationspecific uptake of the labelled carrier.

Radiological imaging of various tissues in the human body is commonlyaccomplished using Technetium-99m. ^(99m)-Tc is a well-known radioactiveisotope used for radiodiagnostics. It emits detectable low level 140 keVgamma rays, has a half life of 6 hours and decays to Tc-99 in 24 hours(93.7%). It is used for imaging and function studies of the brain,myocardium, thyroid, lungs, liver, gallbladder, kidneys, bone, blood,and tumors. It is reported to be used in over 20 million diagnosticnuclear medicine procedures each year.

Targeted radiation therapy using microparticles or microspheres is alsoa well developed field radioisotope therapy. Radionuclides such asYttrium-90 and Holmium-166 are commonly used radioactive beta emittersin microsphere radiotherapy. Polymer microspheres such as albumin,poly-lactic acid derivatives, and so forth, and glass microspheres, areboth generally known in the medical arts for use in delivering bothpharmaceuticals and radiopharmaceuticals to specific tissue sites.

However, a need remains for a radioactive microparticle for delivery ofone or more radiopharmaceuticals and which have characteristics whichwill permit the microparticles to be suitable for injection into apatient for localized imaging or therapy.

BRIEF SUMMARY OF THE INVENTION

In a preferred embodiment there is provided a strontium phosphateradiomicroparticle, made by the process comprising:

-   -   a. reacting a strontium-containing borate glass microparticle        with a phosphate solution of a sufficient concentration and for        a sufficient time under suitable conditions to convert the        strontium-containing borate glass microparticle to a strontium        phosphate microparticle; and    -   b. bonding at least one radioisotope suitable for radioimaging        and/or radiotherapy to said strontium phosphate microparticle.

In other preferred embodiments, there are provided additional featuresavailable singularly and in combination.

In one preferred process, there is provided wherein thestrontium-containing borate glass microparticle is a microsphere havinga diameter of about 20 μm to about 50 μm.

In one preferred process, there is provided wherein the strontiumphosphate microparticle has a surface area of between about 90 to about200 square meters per gram.

In one preferred process, there is provided wherein the at least oneradioisotope is a therapeutic beta-emitting radioisotope; and/or whereinthe at least one radioisotope is a diagnostic gamma-emittingradioisotope; and/or wherein the at least one radioisotope is acombination of a therapeutic beta-emitting radioisotope and a diagnosticgamma-emitting radioisotope.

In one preferred process, there is provided wherein the step of bondingsaid at least one radioisotope suitable for radioimaging and/orradiotherapy to the strontium phosphate microparticle is prepared insitu in a clinical setting by mixing just prior to the time ofadministration to a patient said strontium phosphate microparticle withthe at least one radioisotope suitable for radioimaging and/orradiotherapy.

In one preferred process, there is provided wherein the at least oneradioisotope is Technetium-99m; and/or wherein the at least oneradioisotope is selected from the group consisting essentially ofTechnetium-99m, Indium-111, Lutetium-177, Samarium-153, Yttrium-90, andmixtures thereof.

In another preferred embodiment, there is provided a strontium phosphateradiomicroparticle made according to the process described herein.

In one preferred radiomicroparticle, there is provided wherein the atleast one radioisotope comprises at least two different radiosotopes;and/or wherein the at least one radioisotope comprises at least threedifferent radioisotopes.

In another preferred embodiment, there is provided a method ofadministering strontium-phosphate radiomicroparticles to a patient inneed thereof, comprising locally delivering by catheter or suitableintravenous injection to a tissue target or organ of the patient acomposition comprising strontium-phosphate microparticles with at leastone radioisotope bonded thereto and a physiologically acceptablecarrier.

In other preferred methods, there are provided additional featuresavailable singularly and in combination.

In one preferred method, there is provided wherein the at least oneradioisotope is a radiodiagnostic agent; and/or wherein the at least oneradioisotope is a radiotherapeutic agent; and/or wherein the at leastone radioisotope comprises a radiodiagnostic agent and aradiotherapeutic agent.

In one preferred method, there is provided wherein the at least oneradioisotope comprises at least two different radiosotopes; and/orwherein the at least one radioisotope comprises at least three differentradioisotopes.

In one preferred method, there is provided wherein the at least oneradioisotope is technetium-99m; and/or wherein the at least oneradioisotope is selected from the group consisting essentially ofTechnetium-99m, Indium-111, Yttrium-90, Lutetium-177, Samarium-153, andmixtures thereof; and/or wherein the composition also contains anadditional radiotherapeutic agent.

In one preferred method, there is provided wherein the tissue target ororgan is selected from the group consisting of: brain, myocardium,thyroid, lung, liver, spleen, gallbladder, kidney, bone, blood, and headand neck tumor, prostate, breast, and uterine.

In one preferred method, there is provided wherein the strontiumphosphate microparticles with at least one radioisotope are prepared insitu in a clinical setting by mixing just prior to the time ofadministration to a patient said strontium phosphate microparticle withthe at least one radioisotope suitable for radioimaging and/orradiotherapy.

In another preferred embodiment, there is provided a method of obtaininga radiologic image of a specific tissue or organ of a patient,comprising administering by catheter or suitable intravenous injectionto a tissue target or organ of the patient a composition containingstrontium-phosphate microparticles with at least one radiodiagnosticagent bonded thereto in a physiologically acceptable carrier, andobtaining the radiologic image of the specific tissue or organ of thepatient by capturing the gamma radiation emitted by the radiodiagnosticagent using a suitable radionuclide imaging technique.

Additional features of this method include: wherein the at least oneradioisotope is a radiodiagnostic agent; wherein the radiodiagnosticagent is Technetium-99m; and wherein the tissue target or organ isselected from the group consisting of: brain, myocardium, thyroid, lung,liver, spleen, gallbladder, kidney, bone, blood, and head and necktumor, prostate, breast, and uterine.

In other preferred embodiments, there are provided additional featuresavailable singularly and in combination, including: wherein thestrontium-containing borate glass microparticle is fully converted to astrontium phosphate microparticle through to the interior, or wherein itis partially converted to create a porous layer over an unconvertedglass core; wherein the strontium-containing borate glass microparticleis between about 20 and about 40 microns in diameter; wherein thestrontium phosphate microparticle is amorphous or crystalline; whereinthe strontium phosphate microsphere is porous; and wherein thestrontium-containing borate glass microsphere is fully converted to astrontium phosphate microparticle. In some embodiments, thestrontium-containing borate glass microparticle may be substantiallycalcium-free.

In another preferred embodiment, the at least one radioisotope is anyapproved radiopharmaceutical available to nuclear medicinepractitioners.

In a further preferred embodiment, the method further comprises whereinthe radionuclide imaging technique is single photon emission computedtomography (SPECT).

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, novel porous strontiumphosphate microparticle carriers have been devised for use in theimaging and/or treatment of certain cancers, tumor bearing tissue,rheumatoid arthritis, or other diseases where nuclear medicine imagingor treatment is indicated. These carriers constitute microparticles thatcomprise a porous strontium-phosphate material having one or moreradiopharmaceuticals bound to the surface. Both radiodiagnostic gammaemitting agents and radiotherapeutic beta emitting agents arecontemplated.

Overview

The strontium phosphate radiomicroparticle of the present invention ismade by reacting a strontium-containing borate glass microparticle witha phosphate solution in amounts and for a sufficient time under suitableconditions to convert the strontium-containing borate glassmicroparticle to a strontium phosphate microparticle, and bonding atleast one radioisotope suitable for radioimaging and/or radiotherapy ina mammal to said strontium phosphate microparticle.

The phosphate solution conversion process converts a solid strontiumborate glass into a porous strontium phosphate material. Bymanufacturing a non-radioactive solid strontium-containing borate glassmicroparticle of a specific diameter, the conversion results in a porousstrontium phosphate microparticle of a specific diameter. Due to thesubstantially thorough chemical action of the phosphate solution on theborate glass, a substantially pure porous strontium phosphate materialhaving a high surface area is achieved in the location where thephosphate solution has reacted with the borate glass.

The porosity of the resulting strontium phosphate material and thecontrollable size and number of the microparticles provide an excellentdelivery platform for delivering compounds of interest to specificlocations. Thus, the process of manufacturing of the microsphere hasbeen divorced from the process of adding the radiolabel orradiotherapeutic. This provides nuclear medicine professionals theability to control the radiodiagnostic and radiotherapeutic regimen byallowing, in the clinical setting, at or near the time of delivery, thedecision of the type and quantity of radiopharmaceutical(s) to beincorporated into the delivery vehicle.

Advantages

Some of the advantages provided by this approach include: the ability toadsorb a radioisotope or combination of radioisotopes onto a porousmicroparticle, the ability to customize dose to the patient, customizeimaging of the tissue, reducing time-related degradation of theactivated radiopharmaceutical, and reducing exposure to medicalpersonnel.

An additional advantage provided by this approach includes an increasein radio-opacity which provides clearer radiographic images due to theuse of strontium phosphate rather than calcium apatite.

A further advantage provided by this approach includes the ability toblend two or more different radioisotopes. Further, this allows for thetherapy to be able to change over time, or be customized to a particularset of circumstances.

A further advantage is the ability to use radioisotopes that have ashort half life and to avoid using microparticle manufacturing processesthat would vaporize certain radioisotopes such as Technetium andRhenium.

Porosity

Importantly, the strontium phosphate microparticles achieve a porosity,or surface area, that allows for a significant amount of radioisotope tobe bound. It is contemplated that surface area values of 90 to 200square meters per gram are within the scope of the present invention.Significantly, prior art attempts using calcium apatite to create themicroparticles have provided much lower surface area values of only 40sq. meters per gram, or less. Further, these calcium-only microparticlesdemand complex manufacturing that includes a two-step process to adsorbthe isotope requiring a binder, a heating step that destroys the surfacearea, and chemical precipitation.

These radioactive substantially spherical strontium phosphateradiomicroparticles are made by reacting a pre-made strontium-containingborate glass microparticle with a phosphate solution in amounts and fora sufficient time under suitable conditions to convert, partially orfully, the strontium-containing borate glass microparticle to anamorphous or crystalline strontium phosphate microparticle. Once theglass has been converted and the porous material is made, aradioisotope-bearing radiopharmaceutical is then adsorbed or bonded tothe substantially pure strontium phosphate microparticle and is thensuitable for radioimaging and/or radiotherapy in a mammal.

Phosphate Conversion

The phosphate solution conversion process converts a solid strontiumborate glass microparticle into a porous strontium phosphate materialthat can be either amorphous or crystalline. The glass can be convertedcompletely thus forming a completely porous or even hollowmicroparticle. The glass can also be partially converted thus resultingin a glass core surrounded by a porous strontium phosphate layer. Theconversion of the borate glass is performed by exposing it to an aqueousphosphate solution. Many different phosphate solutions are contemplatedas within the scope of the present invention. One non-limiting exampleincludes phosphate buffered saline (PBS). PBS may be prepared in manydifferent ways. Some formulations do not contain potassium, while otherscontain calcium or magnesium. Generally, PBS contains the followingconstituents: 137 mM NaCl, 2.7 mM KCl, 10 mM sodium phosphate dibasic, 2mM potassium phosphate monobasic and a pH of 7.4. Another non-limitingexample is a 0.25 M K₂PO₄ solution. Non-saline phosphate solutions maybe prepared using monosodium phosphate (NaH₂PO₄), disodium phosphate(Na₂HPO₄), and water, with phosphoric acid or sodium hydroxide to adjustthe pH as desired. Other concentrations and types of aqueous phosphatesolutions are contemplated as within the scope of the invention.

Strontium

Conversion of the strontium borate glass results, at the molecularlevel, in a high surface-area porous material, that itself, is anagglomeration containing the strontium phosphate compound. The pores ofthe surface provide access to the strontium phosphate compound. When aradioisotope is mixed with the microparticles, a strong chemical bond ismade with the exposed strontium phosphate compound. Without being heldto any particular chemical reaction or theory, it is believed that theisotope can bind in a substitution reaction removing a phosphate [PO₄group], or it may be bound into a void space or it may substitute for astrontium ion [Sr⁺²].

Microparticle Size and Shape

By manufacturing a non-radioactive solid strontium-containing borateglass microparticle of a specific diameter, the conversion results in aporous strontium phosphate microparticle of a specific diameter. Sincethe starting material is a solid strontium-containing borate glassmicroparticle and it becomes fully (or partially) converted to a porousstrontium phosphate microparticle, the physical parameters of shape,size, diameter are dictated by the glass microparticle manufacturingprocess. Importantly, the size and dimension of the converted strontiummicroparticle are substantially the same as the size and dimension ofthe starting strontium borate glass microparticle. This feature providesthe significant advantage of being able to control the size anddimension of the delivery vehicle itself, the porous strontium phosphatemicroparticle.

“Microparticle”, as used herein, generally refers to a particle of arelatively small size, but not necessarily in the micron size range; theterm is used in reference to particles of sizes that can be less than 50nm to 1000 microns or greater. “Radiomicroparticle” refers to themicroparticles of the present invention with one or more radioisotopesadsorbed thereon. The microparticles are preferably round spheroidshaving a preferred diameter of about 20 μm and above. In other preferredembodiments, the microparticles range from about 20 μm to about 200 μm,from about 30-80 μm, from about 20-40 μm, and from about 25 μm to 38 μm.In another embodiment, the diameter of the particles is from about 5 toabout 100 microns, preferably from about 10 to about 50 microns. As usedherein, the microparticle encompasses microspheres, microcapsules,ellipsoids, fibers, and microparticles, unless specified otherwise.

Customized Delivery

The porosity of the resulting strontium phosphate material and thecontrollable size and number of the microparticles provide an excellentdelivery platform for delivering radiation to specific locations.

Importantly, no radioisotope is incorporated in the borate glassmicroparticle. Thus, the process of manufacturing of the microsphere hasbeen divorced from the process of adding the radioisotope label or theradiotherapeutic. Prior radiomicrospheres must be manufactured as glassor biopolymer particles with the radioisotope as a homogeneous integralcomponent of the glass or biopolymer. The present inventive approachprovides a medical radiology professional the ability to control theradiodiagnostic and radiotherapeutic regimen by allowing them, in theclinical setting, to decide the type and quantity ofradiopharmaceutical(s) to incorporate into the delivery vehicle. Some ofthe advantages of this approach include the ability to customize thedose to the patient, customize imaging of the tissue, reducingtime-related degradation of the activated radiopharmaceutical, andreducing exposure to medical personnel.

Delivery of Multiple Isotopes

Importantly, the combination of the significantly increased surface areaand the electrical attraction of the radioisotope to the porousmicroparticle provides for bonding multiple radioisotopes to themicroparticle. In preferred embodiments, two radiosisotopes are bound.Binding a first isotope to the porous microparticle is performed usingsimple mixing in an appropriate solution over a pre-determined time, andthen washing and eluting out the unbound isotope. This provides acomposition where a radioisotope is bound to the microparticles.

Binding a second isotope to the porous microparticle is performed bysimple mixing in a solution having the second isotope. Importantly, thesecond isotope does not displace the first isotope since themicroparticles have a large surface area, and a nuclear pharmacist orother professional can take advantage of the different bindingcapacities of various radisotopes to the microparticles. Thus, three andeven four different radioisotopes can be bound within a single dose, orbatch, of microparticles.

Further, by using radiation dosimeters which show the keV peaks ofvarious radioisotopes, activity can be tested, and tailored to aspecific therapy. For example, treatment could in one non-limitingexample consist of 100 units of isotope #1 and 50 units of isotope #2.

Delivery to Tissue

The microparticles may be administered to the patient through the use ofcatheters either alone or in combination with vasoconstricting agents orby any other means of administration that effectively causes themicroparticles to become embedded in the cancerous or tumor bearingtissue. For purposes of administration, the microparticles arepreferably suspended in a medium that has a sufficient density orviscosity that prevents the microparticles from settling out ofsuspension during the administration procedure. Presently preferredliquid vehicles for suspension of the microparticles includepolyvinylpyrrolidone (PVP), sold under the trade designation PlasdoneK-30 and Povidone by GAF Corp, a contrast media sold under the tradedesignation Metrizamide by Nyegard & Co. of Oslo, Norway, a contrastmedia sold under the trade designation Renografin 76 by E. R. Squibb &Co., 50% dextrose solutions and saline.

Types of Radioisotopes

In a preferred embodiment of the present invention, theradioisotopes/radionuclides are chosen so that when administered to thepatient, the microparticles may emit either beta radiation, gammaradiation, or both. The beta emitter is chosen to deliver a therapeuticintensity and therapeutic amount of short-range (e.g., a penetration ofthe tissue on the order of about several millimeters or less) betaradiation but does not emit a significant amount of unwanted betaradiation which could have a negative impact on healthy tissuesurrounding the cancerous or tumor bearing tissue. The gamma emitter ischosen to deliver a diagnostic intensity and diagnostic amount oflonger-range (e.g., capable of external detection) gamma radiation butdoes not emit a significant amount of unwanted gamma radiation.

Since the radioisotopes/radionuclides may be bonded or prepared in situjust prior to delivery by a radiology professional, the type ofradioisotope(s) may be chosen based on each patient's needs anddiagnosis. By providing a patient-specific dosing, patient outcome isimproved and side-effects are minimized. Patient data such as age,gender, weight, and pre-existing conditions are considered whendetermining a radiotherapeutic and/or radiodiagnostic profile. Cancerdata such as tumor size, tumor type, tumor location, degree of surgicalintervention and success, vascular structures within and adjacent to thearea being treated, and organ involvement are also considered whendetermining a radiotherapeutic and/or radiodiagnostic profile.

The radioisotope Yttrium-90 which form radioisotopes having a half-lifegreater than about two days and less than about 30 days is oneparticularly preferred therapeutic radioisotope which emit therapeuticbeta radiation.

For radioimaging, the radioisotope technetium-99m is particularlypreferred.

The present invention includes wherein the radioisotope isradiopharmaceutical grade and is selected from the group consistingessentially of, but not limited to: Actinium-225, Antimony-127,Arsenic-74, Barium-140, Bismuth-210, Californium-246, Calcium-46,calcium-47, Carbon-11, Carbon-14, Cesium-131, Cesium-137, Chromium-51,Cobalt-57, Cobalt-58, Cobalt-60, Dysprosium-165, Erbium-169,Fluorine-18, Gallium-67, Gallium-68, Gold-198, Hydrogen-3, Indium-111,Indium-113m, Iodine-123, Iodine-125, Iodine-131 Diagnostic, Iodine-131Therapeutic, Iridium-192, Iron-59, Iron-82, Krypton-8 m, Lanthanum-140,Lutetium-177, Molybdenum-99, Nitrogen-13, Oxygen-15, Paladium-103,Phosphorus-32, Radon-222, Radium-224, Rhenium-186, Rhenium-188, Rb-82,Samarium-153, Selenium-75, Sodium-22, Sodium-24, Strontium-89,Technetium-99m, Thallium-201, Xenon-127, Xenon-133, Yttrium-90, andcombinations, and mixtures thereof.

Where combinations of radioisotopes are used with the microparticles,preferred combinations of radioisotopes include having one or more betaemitters along with one or more gamma emitters. Examples include but arenot limited to Y-90/In-111, Y-90/Tc-99m, P-32/In-111, P-32/Tc-99m,Ho-166/In-111, Ho-166/Tc-99m, Sm-153/In-111, and Sm-153/Tc-99m.

Particularly preferred radioisotopes include Technetium-99m andIndium-111 (radiodiagnostic gamma emitters), Lutetium-177 (being both abeta and gamma emitter), and Samarium-153 and Yttrium-90(radiotherapeutic beta emitters). Tc-99m has been used for imaging andfunction studies of the brain, myocardium, thyroid, lungs, liver,gallbladder, kidneys, bone, blood, and tumors. Indium-11 pentetreotidehas been used in imaging of neuroendocrine tumors that overexpresssomatostatin receptors and has become standard for localization of thesetumors. This radioligand is internalized into the cell and can inducereceptor-specific cytotoxicity by emission of Auger electrons.Lutetium-177 having both gamma and beta properties enables its use inimaging as well as treatment. It has a shorter radius of penetrationthat Y-90 which makes it an ideal candidate for radiotherapy of smalltumors. Samarium-153 lexidronam (chemical name Samarium-153-ethylenediamine tetramethylene phosphonate, abbreviated Samarium-153 EDTMP,trade name Quadramet) is a complex of a radioisotope of the lanthanideelement samarium with the chelator EDTMP. It has been used to treatcancer pain when cancer has spread to the bone. Once injected into avein, it distributes throughout the body and localizes in areas wherecancer has invaded the bone, allowing the beta particles (electrons) todestroy the nearby cancer cells. It is also commonly used in lungcancer, prostate cancer, breast cancer, and osteosarcoma. Yttrium-90 hasbeen used in the treatment of various cancers including lymphoma,leukemia, ovarian, colorectal, pancreatic, and bone cancers, and intreatment of rheumatoid arthritis by radionuclide synovectomy.

Although an attempt is made to provide an exhaustive list, it iswell-known to nuclear medicine specialists that radioisotopes may beproduced using a generator system like Mo-Tc or Sn/In systems, a thermalneutron reactor, a cyclotron, or fission produced. Accordingly, anyradioisotopes with functional equivalents to those listed are intendedto be encompassed wherever appropriate within the scope of the presentinvention.

Glass Preparation

The microparticles of the present invention may be prepared from ahomogenous mixture of powders (i.e., the batch) that is melted to formthe desired glass composition. The exact chemical compounds or rawmaterials used for the batch is not critical so long as they provide thenecessary oxides in the correct proportion for the melt compositionbeing prepared. For instance, for making a strontium borate glass, thenstrontium, borate, and/or soda, powders may be used as some the batchraw materials. The purity of each raw material is preferably greaterthan 99.9%. After either dry or wet mixing of the powders to achieve ahomogeneous mixture, the mixture may be placed in a platinum cruciblefor melting. High purity alumina crucibles can also be used if at leastsmall amounts of alumina can be tolerated in the glass being made. Thecrucibles containing the powdered batch are then placed in an electricfurnace which is heated 1000.degree. to 1600.degree. C., depending uponthe composition. In this temperature range, the batch melts to form aliquid which is stirred several times to improve its chemicalhomogeneity. The melt should remain at 1000.degree. to 1600.degree. C.till all solid material in the batch is totally dissolved, usually 4-10hours being sufficient. Significantly, by not incorporating theradioisotope into the melt, no radioisotope can be vaporized, thusavoiding a radiation hazard.

Another advantage of the invention is the ability to use radioisotopesthat have a shorter half-life. For example, Tc-99m (Technetium-99m)cannot be made part of the glass, i.e. the half-life may often be tooshort to be useful when it is incorporated as part of certainhomogeneous glass-radioisotope compositions. Additionally, the abilityto use radioisotopes that would otherwise be destroyed or degrade by theglass-melt process. For example, trying to incorporate Technetium orRhodium into a melt would vaporize the Technetium or Rhodium.

When melting and stirring is complete, the crucible is removed from thefurnace and the melt is quickly quenched to a glass by pouring the meltonto a cold steel plate or into clean, distilled water. This procedurebreaks the glass into fragments, which aids and simplifies crushing theglass to a fine powder. The powder is then sized and spheroidized foruse.

Spheroidizing

To obtain spheroid microparticles having a diameter in the desired rangeof micrometers, the glass is processed using varying techniques such asgrinding and passing through mesh sieves of the desired size, where theglass particles may be formed into spheroids by passing the sizedparticles through a gas/oxygen flame where they are melted and aspherical liquid droplet is formed by surface tension. A vibratoryfeeder located above the gas/oxygen burner slowly vibrates the powderinto a vertical tube that guides the falling powder into the flame at atypical rate of 5-25 gm/hr. The flame is directed into a metal containerwhich catches the spheroidized particles as they are expelled from theflame. The droplets are rapidly cooled before they touch any solidobject so that, their spherical shape is retained in the solid product.

After spheroidization, the glass spheres are preferably collected andrescreened based upon size. As a non-limiting example, when themicroparticles are intended to be used in the treatment of liver cancer,the fraction less than 30 and greater than 20 micrometers in diameter isrecovered since this is a desirable size for use in the human liver.After screening, the −30/+20 microparticles are examined with an opticalmicroscope and are then washed with a weak acid (HCl, for example),filtered, and washed several times with reagent grade acetone. Thewashed spheres are then heated in a furnace in air to 500-600 degree C.for 2-6 hours to destroy any organic material.

The final step is to examine a representative sample spheres in ascanning electron microscope to evaluate the size range and shape of thespheres. The quantity of undersize spheres (less than 10 micrometers indiameter) is determined along with the concentration of non-sphericalparticles. The composition of the spheres can be checked by energydispersive x-ray analysis to confirm that the composition is correct andthat there is an absence of chemical contamination.

The glass microparticles are then ready for phosphate conversion,bonding with radionuclide, and subsequent administration to the patient.

In accordance with the present invention, the above processing steps aremerely exemplary and do not in any way limit the present invention.Similarly, the present invention is not limited to glass microparticleshaving a size described above; the size of the microparticles of thepresent invention may be varied according to the application.

Types of Cancers

The microparticles of the present invention may be used in a variety ofclinical situations, including but not limited to: selective internalradiation therapy for tumors of areas that have favorable vasculature,including the liver, spleen, brain, kidney, head & neck, uterine, andprostate. The microparticles may also be used for imaging, including aLiver/Spleen Scan—for tumors, cysts or hepatocellular disease; a BrainScan—for tumors, trauma, or dementia; a Tumor Scan for malignant tumorsor metastatic disease of the Kidney, Head & Neck, Uterine/Gynecological;and any Scan or Therapy having favorable vasculature for this approach.

One radionuclide imaging technique contemplated as within the scope ofthe invention is single photon emission computed tomography (SPECT).

Since most organs, besides the liver, have only one blood vessel thatfeeds it, administration may be performed by delivery to that mainfeeder artery and allowing the microparticles to lodge in the capillarybed since they are too large to move through the capillary. The livermay require a specialized delivery regimen. In another embodiment, thevessel that feeds the tumor may be identified, and this artery is usedto deliver the microparticles.

As various changes could be made in the above methods and products,without departing from the scope of the invention, it is intended thatall matter contained in the above description or shown in anyaccompanying drawings shall be interpreted as illustrative and not in alimiting sense. Any references recited herein are incorporated herein intheir entirety, particularly as they relate to teaching the level ofordinary skill in this art and for any disclosure necessary for thecommoner understanding of the subject matter of the claimed invention.It will be clear to a person of ordinary skill in the art that the aboveembodiments may be altered or that insubstantial changes may be madewithout departing from the scope of the invention. Accordingly, thescope of the invention is determined by the scope of the followingclaims and their equitable Equivalents.

What is claimed is:
 1. A crystalline strontium phosphateradiomicroparticle comprising: a crystalline strontium phosphatemicroparticle with at least one radioisotope suitable for radioimagingand/or radiotherapy bonded to the surface thereof, wherein thecrystalline strontium phosphate microparticle has a surface area ofbetween about 90 and about 200 square meters per gram.
 2. Thecrystalline strontium phosphate radiomicroparticle of claim 1, whereinthe crystalline strontium phosphate microparticle has a diameter ofabout 20 μm to about 200 μm.
 3. The crystalline strontium phosphateradiomicroparticle of claim 1, wherein the bonded radioisotope is atherapeutic beta-emitting radioisotope.
 4. The crystalline strontiumphosphate radiomicroparticle of claim 1, wherein the bonded radioisotopeis a diagnostic gamma-emitting radioisotope.
 5. The crystallinestrontium phosphate radiomicroparticle of claim 1, wherein the bondedradioisotope comprises a combination of a therapeutic beta-emittingradioisotope and a diagnostic gamma-emitting radioisotope.
 6. Thecrystalline strontium phosphate radiomicroparticle of claim 1, whereinthe bonded radioisotope is Technetium-99m.
 7. The crystalline strontiumphosphate radiomicroparticle of claim 1, wherein the bonded radioisotopeis selected from the group consisting essentially of Technetium-99m,Indium-111, Lutetium-177, Samarium-153, Yttrium-90, and mixturesthereof.
 8. The crystalline strontium phosphate radiomicroparticle ofclaim 1, wherein the bonded radioisotope comprises at least twodifferent radioisotopes.
 9. The crystalline strontium phosphateradiomicroparticle of claim 1, wherein the bonded radioisotope comprisesat least three different radioisotopes.
 10. A method of administeringcrystalline strontium-phosphate radiomicroparticles to a patient in needthereof, comprising: locally delivering the crystalline strontiumphosphate radiomicroparticles in a physiologically acceptable carrier bycatheter or suitable intravenous injection to a tissue target or organof the patient, wherein the crystalline strontium phosphateradiomicroparticles comprise crystalline strontium phosphatemicroparticles with at least one radioisotope suitable for radioimagingand/or radiotherapy bonded to the surfaces thereof, and wherein thecrystalline strontium phosphate microparticles have a surface area ofbetween about 90 to about 200 square meters per gram.
 11. The method ofclaim 10, wherein the bonded radioisotope is a radiodiagnostic agent.12. The method of claim 10, wherein the bonded radioisotope is aradiotherapeutic agent.
 13. The method of claim 10, wherein the bondedradioisotope comprises a radiodiagnostic agent and a radiotherapeuticagent.
 14. The method of claim 10, wherein the bonded radioisotopecomprises at least two different radioisotopes.
 15. The method of claim10, wherein the bonded radioisotope comprises at least three differentradioisotopes.
 16. The method of claim 10, wherein the bondedradioisotope is technetium-99m.
 17. The method of claim 10, wherein thebonded radioisotope is selected from the group consisting essentially ofTechnetium-99m, Indium-111, Yttrium-90, Lutetium-177, Samarium-153, andmixtures thereof.
 18. The method of claim 10, wherein the compositionalso contains an additional radiotherapeutic agent.
 19. The method ofclaim 10, wherein the tissue target or organ is selected from the groupconsisting of brain, myocardium, thyroid, lung, liver, spleengallbladder, kidney, bone, blood, head and neck, prostate, breast anduterine.
 20. The method of claim 10, wherein the crystalline strontiumphosphate microparticles with at least one radioisotope suitable forradioimaging and/or radiotherapy bonded to the surface thereof areprepared in situ in a clinical setting by mixing just prior to the timeof administration to a patient.
 21. A method of obtaining a radiologicimage of a specific tissue or organ of a patient, comprising:administering crystalline strontium phosphate radiomicroparticles in aphysiologically acceptable carrier by catheter or suitable intravenousinjection to a tissue target or organ of the patient and obtaining theradiologic image of the specific tissue or organ of the patient bycapturing the gamma radiation emitted by the radiodiagnostic agent usinga suitable radionuclide imaging technique, wherein the crystallinestrontium phosphate radiomicroparticles comprise crystalline strontiumphosphate microparticles with at least one radioisotope suitable forradioimaging bonded to the surface thereof, and wherein the crystallinestrontium phosphate microparticles have a surface area of between about90 to about 200 square meters per gram.
 22. The method of claim 21,wherein the radiodiagnostic agent is Technetium-99m.
 23. The method ofclaim 21, wherein the tissue target or organ is selected from the groupconsisting of brain, myocardium, thyroid, lung, liver, spleen,gallbladder, kidney, bone, blood, head and neck, prostate, breast anduterine.
 24. The method of claim 21, wherein the radionuclide imagingtechnique is single photon emission computed tomography (SPECT).
 25. Themethod of claim 21, wherein the radiodiagnostic agent is selected fromthe group consisting essentially of Technetium-99m, Indium-111,Lutetium-177, and mixtures thereof.